1H-s-triazolo[4,3-a][1,5]benzodiazepin-1,5(6H)-diones

ABSTRACT

Compounds of the following formula ##STR1## are useful as central nervous system depressants, tranquilizers, sedatives and muscle relaxants.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide new compounds whichare useful as central nervous system depressants, tranquilizers,sedatives and muscle relaxants. Another object is to provide methods forthe preparation of these compounds. Another object is to providecompositions for the administration of the compounds of the invention.These and other objects of the present invention will be apparent fromthe following description.

SUMMARY OF THE INVENTION

It has now been found that1H-s-triazolo[4,3-a][1,5]-benzodiazepin-1,5(6H)-diones of the followingformula ##STR2## are useful CNS depressants, tranquilizers, sedatives,and muscle relaxants in mammalian species.

DETAILED DESCRIPTION

The novel 1H-s-triazolo[4,3-a][1,5]benzodiazepin-1,5(6H)-diones offormula 1 are useful CNS depressants, tranquilizers and sedatives. Thecompounds of formulas 2-12, and the novel compounds of formula 7 areintermediates for the compounds of formula 1. ##STR3## In the foregoingformulas

R' is H; alkyl of 1-3 carbons optionally substituted by amino, bymono-alkylamines wherein the alkyl radical contains 1-3 carbons, bydialkylamino wherein the alkyl radicals contain 1-3 carbons, by phenylwherein the phenyl ring is optionally substituted by one or more Dgroups wherein D is as defined below; or phenyl wherein the phenyl ringis optionally substituted by one or more D groups wherein D is asdefined below;

R² is H, alkyl of 1-3 carbons, hydroxy or acyloxy (1-4 carbons).

X and Y can be the same or different and are hydrogen, F, Cl, Br,trifluoromethyl, alkyl of from 1-4 carbons, alkoxy of from 1-4 carbons,nitro, cyano, amino, alkanoylamino of 1-4 carbons, alkylthio of 1-4carbons, alkylsulfinyl of 1-4 carbons or alkyl sulfonyl of 1-4 carbons;

D can be alkyl of 1-3 carbons; halogen, preferably bromine and chlorine;trifluoromethyl; alkoxy of 1-3 carbons; and nitro.

R⁴ is alkyl of 1-3 carbons optionally substituted by amino,monoalkylamino of 1-3 carbons, dialkylamino of 1-3 carbons, and phenylwherein the phenyl ring is optionally substituted by one or more groupsas defined for D.

R³ is alkyl of from 1-4 carbons, benzyl or phenethyl;

n is 0, 1 or 2;

R⁵ is a group of formula ##STR4## where P and Q may be the same ordifferent and may be hydrogen or phenyl optionally substituted by one ormore groups as defined for D, with the proviso that at least one of Pand Q is aryl.

R⁶ is alkyl of 1-4 carbons optionally substituted by phenyl.

SYNTHESIS

The 1H-s-triazolo[4,3-a][1,5]benzodiazepin-1,5(6H)-diones of formula 1can be prepared by several methods.

One method (hereinafter called the first method) for the synthesis ofcompounds of formula 1 wherein R' is hydrogen involves reacting acompound of formulas 2-6 with from about 0.8 to about 6.0, preferablyfrom about 1.0 to about 3.0 molar equivalents of an alkyl carbazate offormula ##STR5## (where R⁶ is as defined previously) either alone or,preferably, in an inert, organic solvent or mixture of solvents. Typicalorganic solvents which may be used in the above reaction include arylhydrocarbons, e.g., benzene, toluene, xylene and the like; chlorinatedhydrocarbons such as di-, tri-, tetrachloroethanes and the like; lowermolecular weight alkanols of 1-4 carbons such as ethanol, tertiary butylalcohol, n-butanol and the like; N,N-dialkylformamides,N,N-dialkylalkanoyl amides wherein the alkyl and alkanoyl radicals have1-4 carbons, such as dimethylformamide, dimethylacetamide and the like;hexamethylphosphorous triamide, ethers, such as dioxane and the like anddi-lower alkyl sulfoxides, such as dimethyl sulfoxide and the like. Thereaction is carried out at from about 40° C. to about 320° C.,preferably from about 80° C., to about 250° C., until a significantamount of end product is obtained, typically, for from about 1/4 toabout 92 hours, preferably from about 1 to about 48 hours.

The final product of formula 1 wherein R' is hydrogen is isolated byconventional techniques. For example, the reaction mixture is evaporatedand the residue is partitioned between aqueous sodium bicarbonate and awater-immiscible inert, organic solvent, such as halogenatedhydrocarbons, e.g., methylene chloride, chloroform or trichloroethylene;alkyl esters wherein both the acid and alcohol from which the ester isderived may have from 1 to 4 carbon atoms, e.g., ethyl acetate, propylacetate, ethyl propionate and the like. The organic solvent is washedwith water, dried and chromatographed.

Another method for the synthesis of compounds of formula 1 wherein R' ishydrogen involves heating compounds of formula 7 either alone or in aninert, organic solvent at from about 60° C. to about 350° C., preferablyfrom about 80° C. to about 300° C. for from about 1/2 to about 72 hours,preferably from about 1/6 to about 12 hours. Typical inert, organicsolvents that are used are those defined in the first method. Theproducts are isolated by conventional techniques. For example, thereaction is diluted with a water-immiscible, inert, organic solvent,washed with water, dried and chromatographed.

Another method (hereinafter called the third method) of synthesis forcompounds of formula 1 wherein R' is hydrogen involves reactingcompounds of formula 8 with from about 0.8 to about 6, preferably fromabout 1 to about 3, molar equivalents of acyl derivatives of formula##STR6## (where W is --OR⁶ or halogen, preferably chlorine or bromine),in the presence of a tertiary amine base in an optional inert organicsolvent. Typical inert organic solvents which may be used include arylhydrocarbons such as benzene, toluene, xylene and the like; chlorinatedhydrocarbons such as tri- and tetrachloroethanes and the like; etherssuch as 1,2-dimethoxyethane, tetrahydrofuran, dioxane and the like;N,N-dialkylformamides and N,N-dialkyl alkanoylamides wherein the alkyland alkanoyl radicals have 1-4 carbons such as dimethylformamide,dimethylacetamide and the like. Typical tertiary bases include pyridineand the like and triethylamine and the like. The reaction conditions andthe isolation of the products are as described in the first method.

Compounds of formula 1 where R' is alkyl of 1-3 carbons substituted byamino, by mono-alkylamino of 1-3 carbons, by di-alkylamino of 1-3carbons or by phenyl optionally substituted by one or more D groups, areprepared by reacting compounds of formula 1 where R' is hydrogen withfrom about 0.5 to about 12, preferably from about 0.8 to about 1.2 molarequivalents of an appropriate base, followed by reaction of the thusformed salt with a corresponding molar equivalent of an appropriatesubstituted alkylating agent of formula R⁴ --M where R⁴ is as definedpreviously and M is halogen, preferably chlorine, bromine, iodine;##STR7## or an alkyl or arylsulfonate of formula ##STR8## where R⁷ canbe alkyl of 1-6 carbons or aryl of from about 6 to 10 carbons optionallysubstituted by halogen, nitro or alkyl of 1 to 3 carbons, or R⁴ --M maybe any other alkylating agent (within the definition of R⁴) capable ofintroducing a group as defined for R⁴. The reaction is run in anessentially inert organic solvent.

Typical bases include alkali metal (preferably sodium and potassium)salts as well as thallous salts of lower molecular weight alkanols of1-6 carbons such as methanol, ethanol, propanol, isopropal, t-butanol,amyl alcohol and the like; alkali metal (preferably sodium) hydrides;alkali metals (preferably sodium and potassium); alkali metal(preferably sodium and potassium) salts of acidic hydrocarbons such astriphenylmethane and the like as well as any other base known to thoseskilled in the art capable of generating salts of the acidic hydrogen ofthe triazole ring in compounds of formula 1 wherein R' is hydrogen.Typical organic solvents include those described in the first method.

The reaction is carried out at from about 20° C. to about 300° C.,preferably from about 0° C. to about 100° C. for from about 0.2 hour toabout 96 hours, preferably from about 0.5 hour to about 72 hours.

The products are isolated by conventional techniques. For example thereaction mixture is evaporated; the residue is diluted with awater-immiscible, inert solvent such as methylene chloride, washed withwater, dried and chromatographed.

Compounds of formula 1 wherein R' is phenyl or substituted phenyl can beprepared by reacting compounds of formula 1 wherein R' is hydrogen withat least from about 0.5 to a large excess, preferably at least fromabout 0.8 to about 100, molar equivalents of a phenyl halide, in thepresence of a copper catalyst, in an optional solvent containing fromabout 0.5 to about 1000, preferably from about 0.8 to about 100, molarequivalents of an appropriate hydrogen halide acceptor. The preferredphenyl halides are those of formula AR-K where AR is phenyl optionallysubstituted by one or more groups as defined for D and where K ispreferably chlorine, bromine or iodine. The preferred copper catalystsare powdered copper metal, copper oxides and cuprous and cupric salts.Optional solvents include N,N-dialkylformamides and N,N-dialkyl alkanoylamides wherein the alkyl and alkanoyl radicals have 1-4 carbons such asN,N-dimethylformamide, N,N-dimethylacetamide and the like; dialkylsulfoxides of 2-6 carbons such as dimethyl sulfoxide and the like; andalkylphosphorous triamides of 4-10 carbons such as hexamethylphosphoroustriamide. Appropriate hydrogen halide acceptors include alkali metal(preferably sodium or potassium) carbonates, bicarbonates, or loweralkyl carboxylic acid salts thereof (e.g., acetates). The reaction iscarried out at from about 50° C. to about 200° C., preferably at fromabout 90° C. to about 180° C., for from about 1/4 to about 72 hours,preferably for from about 1/2 to about 14 hours. The product is isolatedin a conventional manner. For example, the reaction mixture is dilutedwith methylene chloride, washed with dilute aqueous ammonium hydroxideand chromatographed.

Compounds of formula 1 where R² is hydroxy are prepared by reactingcompounds of formula 9 with hydrogen in the presence of an appropriatecatalyst, in an inert organic solvent. Typical catalysts includeplatinum, Raney nickel and, preferably, palladium.

Typical solvents include lower alkanols of 1-4 carbons such as methanol,ethanol, and the like; formic acid; lower alkanoic acids of 2-5 carbonssuch as acetic acid and the like as well as other typical solvents wellknown to those versed in the art. Typical hydrogenation pressures arefrom about 0.1 to about 2000 atmospheres, preferably from about 0.8 toabout 100 atmospheres. The reactions are carried out for from about 1/2to about 96 hours, preferably from about 1 to about 72 hours at fromabout 0° C. to about 200° C., preferably from about 20° C. to about 120°C. The products are isolated in a conventional manner. For example thecatalyst is filtered off, the solvent evaporated and the productchromatographed.

Compounds of formula 1 wherein R² is acyl of 1-4 carbons are prepared byreacting compounds of formula 1 wherein R² is hydroxy with from about0.8 to about 6, preferably from about 1 to about 3, molar equivalents ofacyl derivatives of formula ##STR9## (where R⁸ is alkyl of from 1-3carbons and W is halogen, preferably chlorine or bromine or ##STR10##either alone or optionally in an inert organic solvent, in the optionalpresence of a tertiary amine. Typical inert organic solvents which maybe used include aryl hydrocarbons such as benzene, toluene, xylene andthe like; chlorinated hydrocarbons such as tri- and tetrachloroethanesand the like; ethers such as 1,2-dimethoxyethane, tetrahydrofuran,dioxane and the like; N,N-dialkylformamides and N,N-dialkylalkanoylamides wherein the alkyl and alkanoyl radicals have 1-4 carbonssuch as dimethylformamide, dimethylacetamide and the like. Typicaltertiary amines include heterocyclic amines such as pyridine and thelike and trialkyl amines wherein each alkyl radical has from 1-4 carbonatoms such as triethylamine and the like. The reaction conditions andthe isolation of the products are as described in the first method.

Compounds of formula 7 are prepared by reacting compounds of formulas2-6 with from about 0.8 to about 6.0, preferably with from about 1 toabout 3, molar equivalents of an alkyl carbazate of formula ##STR11## inan inert organic solvent. Typical solvents include alkanols of 1-4carbons such as methanol, ethanol, t-butanol, n-butanol and the like;aromatic hydrocarbons such as benzene, toluene, xylene and the like;chlorinated hydrocarbons such as methylene chloride, chloroform, di-,tri- and tetrachloroethane and the like; ethers such as tetrahydrofuran,dioxane, 1,2-dimethoxyethane and the like; N,N-dialkylformamides,N,N-dialkyl alkanoyl amides wherein the alkyl and alkanoyl radicals havefrom 1-4 carbons, such as N,N-dimethyl formamide, N,N-dimethylacetamideand the like; hexamethylenephosphorous triamide and dimethyl sulfoxide.The reaction is carried out at from about -30° C. to about 160° C.preferably at from about 30° C. to about 120° C., until a significantamount of end product is obtained, for from about 1/2 to about 96 hours,preferably for from about 2 to about 12 hours. The products of formula 7are isolated by conventional techniques. For example, the reaction isdiluted with a water-immiscible inert organic solvent, washed withwater, dried and chromatographed.

Another method for the synthesis of compounds of formula 7 involvesreacting compounds of formula 8 with from about 0.5 to about 6,preferably from about 0.8 to about 1.2, molar equivalent of acylderivatives of formula ##STR12## (where W is as defined previously) inan optional inert organic solvent, in the optional presence of atertiary amine.

Typical tertiary amines include heterocyclic amines such as pyridine andthe like and trialkylamines such as triethylamine and the like.

Typical inert organic solvents include those described for the thirdmethod.

The reaction is carried out at from about -30° C. to about 150° C.,preferably from about 0° C. to about 80° C. for from about 1/4 hour toabout 72 hours, preferably from about 1/2 hour to about 14 hours.

The products of formula 7 are isolated by conventional techniques as,for example, described in the first method.

The starting materials of formulas 3-6 and 8 are described in patentapplication Ser. No. 365,012 and references cited therein.

The novel compounds of formula 1 are CNS depressants and are useful as,for example, sedatives, tranquilizers and muscle relaxants in mammalianspecies, e.g., rats, mice and monkeys. Thus, for example, oraladministration of a compound of the invention produces ataxia dosagelevels of from about 50 to about 200 m/kg, specifically in rats at about100 mg/kg.

The compounds of the present invention produce decreased grip strengthat a dosage level of from about 5 to about 50 mg/kg, specifically at adosage level of about 12 mg/kg when administered orally to rats.

The compounds of the present invention have a tranquilizing effect whenadministered orally at a dosage level of from about 2 to about 25 mg/kg,specifically at a dosage level of about 12 mg/kg when administered viathe oral route to rats in a conflict test procedure [cf. J. R. Vogel, B.Beer, D. Clody, Psychopharmacologist 21, 1 (1970)].

The compounds of the present invention in the described dosages may beadministered orally; however, other routes such as intraperitoneally,subcutaneously, intramuscularly or intravenously may be employed.

The active compounds of the present invention are orally administered,for example, with an inert diluent or with an assimilable ediblecarrier, or they may be enclosed in hard or soft gelatin capsules, orthey may be compressed into tablets, or they may be incorporateddirectly with the food of the diet. For oral therapeutic administration,the active compounds of this invention may be incorporated withexcipients and used in the form of tablets, troches, capsules, elixirs,suspensions, syrups, wafers, chewing gum, and the like. The amount ofactive compound in such therapeutically useful compositions orpreparations is such that a suitable dosage will be obtained.

The tablets, troches, pills, capsules and the like may also contain thefollowing: a binder such as gum tragacanth, acacia, corn starch orgelatin; an excipient such as dicalcium phosphate; a disintegratingagent such as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain in addition to materials of theabove type a liquid carrier such as a fatty oil. Various other materialsmay be present as coatings or to otherwise modify the physical form ofthe dosage unit, for instance, tablets, pills or capsules may be coatedwith shellac, sugar, or both. A syrup or elixir may contain the activecompounds, sucrose as a sweetening agent, methyl and propyl parabens aspreservatives, a dye and a flavoring such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit form should bepharmaceutically pure and substantially non-toxic in the amountsemployed.

In the following examples all reactions are run under an inertatmosphere (e.g., argon), at room temperature, using anhydrous solventsunless otherwise indicated; in addition, reactions which are heated aresubsequently cooled to room temperature for work-up. In general,solvents are evaporated in a rotary flash vacuum apparatus. In thispatent application, the full name of the parent ring system of compoundsdescribed as indicated in Column I below is as indicated in Column II.

    ______________________________________                                                I                II                                                   ______________________________________                                        "---1H-s-triazolo[4,3-a][1,5]-                                                                 "---2,4,5,6-tetrahydro-1H-s-                                 benzodiazepine-1,5-dione---"                                                                   triazolo[4,3-a][1,5]-                                                         benzodiazepine-1,5-dione---"                                 "---1H-1,5-benzodiazepin---"                                                                   "---2,3,4,5-tetrahydro-1H-                                                    1,5-benzodiazepin---"                                        "---3H-1,5-benzodiazepin---"                                                                   "---4,5-dihydro-3H-1,5-                                                       benzodiazepin---"                                            ______________________________________                                    

EXAMPLE 18-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dioneMethod A

30.2 g of 7-chloro-5-phenyl-1H-1,5-benzodiazepin-4-one-2-thione and 33.4g of ethyl carbazate in 600 ml dimethylformamide are refluxed withstirring for 24 hours. During this time, argon is bubbled through thereaction mixture. The reaction is evaporated in vacuo and the titlecompound is obtained as described in Example 1, Method B.

Method B

7.50 g of 2-(methylthio)-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-oneand 6.27 g of ethyl carbazate are refluxed in dry dimethylformamide (300ml) while a slow stream of argon is passed through. After 24 hours, thereaction mixture is evaporated to dryness, azeotroped with benzene andtriturated with water (25 ml). The precipitates that formed are filteredoff and dried. This material is chromatographed on a florisil column (10g) eluting successively with methylene chloride (60 ml), CH₂ Cl₂ :EtOAc(6:4, 90 ml) and ethyl acetate (75 ml). The fractions containing theproduct are combined and evaporated to give the title compound. Theproduct is recrystallized from ethyl acetate-hexane.

Method C

3.0 g of 2,7-dichloro-5-phenyl-3H-1,5-benzodiazepin-4-one and 2.5 g ofethyl carbazate in 50 ml of dioxane are refluxed under argon for 24hours. 2 ml of water is then added, the reaction stirred for 1 hour andthe solvent evaporated. The residue is taken up in methylene chloride,washed with dilute aqueous sodium bicarbonate, with water and dried. Thesolvent is evaporated and the residue is chromatographed on ten-1000μsilica gel thick layer plates (20× 20 cm) with ethyl acetate-ethanol(9:1) as eluant. The main band, having an approximate Rf range of0.12-0.28, is removed, stirred with acetone-methanol (9:1) and thesilica gel filtered off. The filtrate is evaporated to give the titlecompound.

Method D

Following the procedure of Example 1, Method B, but substituting 15 g of2-methoxy-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one for 15.8 g of2-(methylthio)-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one in Example1, Method B, the title compound is obtained.

Method E

3 g of 3-(7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one-2-yl) carbazicacid ethyl ester is heated at approximately 50° C. above its meltingpoint under argon for 25 minutes. The reaction is cooled, dissolved inmethylene chloride and purified by column chromatography as describedunder Method B above to give the title compound.

EXAMPLES 2- 27

Following the procedure of Example 1, Method B, but substituting thecompounds indicated in Column I below for2-(methylthio)-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one in Example1, Method B, the compounds indicated in Column II are obtained.

    ______________________________________                                               I                 II                                                   ______________________________________                                         2. 2-(methylthio)-5-phenyl-3H-                                                                     6-phenyl-1H-s-triazolo-                                     1,5-benzodiazepin-4-one                                                                         [4,3-a][1,5]-benzodiazepine-                                                  1,5-dione                                                3. 2-(methylthio)-7-trifluoro-                                                                     8-(trifluoromethyl)-6-phenyl-                               methyl-5-phenyl-3H-1,5-                                                                         1H-s-triazolo[4,3-a][1,5]-                                  benzodiazepin-4-one                                                                             benzodiazepine-1,5-dione                                 4. 2-(methylthio)-7-nitro-5-                                                                       8-nitro-6-phenyl-1H-s-                                      phenyl-3H-1,5-benzodia-                                                                         triazolo[4,3-a][1,5]-                                       zepin-4-one       benzodiazepine-1,5-dione                                 5. 2-(methylthio)-7-methyl-5-                                                                      8-methyl-6-phenyl-1H-s-                                     phenyl-3H-1,5-benzodia-                                                                         triazolo[4,3-a][1,5]-                                       zepin-4-one       benzodiazepine-1,5-dione                                 6. 2-(methylthio)-7-methoxy-                                                                       8-methoxy-6-phenyl-1H-s-                                    5-phenyl-3H-1,5-benzodia-                                                                       triazolo[4,3-a][1,5]benzo-                                  zepin-4-one       diazepine-1,5-dione                                      7. 2-(methylthio)-7-(methyl-                                                                       8-(methylthio)-6-phenyl-                                    thio)-5-phenyl-3H-1,5-                                                                          1H-s-triazolo[4,3-a][1,5]-                                  benzodiazepin-4-one                                                                             benzodiazepine-1,5-dione                                 8. 2-(methylthio)-7-pentyl-5-                                                                      8-pentyl-6-phenyl-1H-s-                                     phenyl-3H-1,5-benzodia-                                                                         triazolo[4,3-a][1,5]benzo-                                  zepin-4-one       diazepine-1,5-dione                                      9. 2-(methylthio)-7-pentoxy-                                                                       8-pentoxy-6-phenyl-1H-                                      5-phenyl-3H-1,5-benzodia-                                                                       s-triazolo[4,3-a][1,5]-                                     zepin-4-one       benzodiazepine-1,5-dione                                10. 2-(methylthio)-7-bromo-5-                                                                       8-bromo-6-phenyl-1H-s-                                      phenyl-3H-1,5-benzodia-                                                                         triazolo[4,3-a][1,5]benzo-                                  zepin-4-one       diazepine-1,5-dione                                     11. 2-(methylthio)-7-fluoro-                                                                        8-fluoro-6-phenyl-1H-                                       5-phenyl-3H-1,5-benzodia-                                                                       s-triazolo[ 4,3-a][1,5]-                                    zepin-4-one       benzodiazepine-1,5-dione                                12. 2-(methylthio)-7-cyano-                                                                         8-cyano-6-phenyl-1H-                                        5-phenyl-3H-1,5-benzodia-                                                                       s-triazolo[ 4,3-a][1,5]-                                    zepin-4-one       benzodiazepine-1,5-dione                                13. 2-(ethylthio)-7-chloro-                                                                         8-chloro-6-phenyl-1H-                                       5-phenyl-3H-1,5-benzodia-                                                                       s-triazolo[4,3-a][1,5]-                                     zepin-4-one       benzodiazepine-1,5-dione                                14. 2-(methylthio)-7-chloro-                                                                        8-chloro-6-(2-fluorophenyl)-                                5-(2-fluorophenyl)-3H-                                                                          1H-s-triazolo[4,3-a][1,5]-                                  1,5-benzodiazepin-4-one                                                                         benzodiazepine-1,5-dione                                15. 2-(methylthio)-7-chloro-                                                                        8-chloro-6-(3-chlorophenyl)-                                5-(3-chlorophenyl)-3H-                                                                          1H-s-triazolo[4,3-a][1,5]-                                  1,5-benzodiazepin-4-one                                                                         benzodiazepine-1,5-dione                                16. 2-(methylthio)-7-chloro-                                                                        8-chloro-6-(4-chlorophenyl)-                                5-(4-chlorophenyl)-3H-                                                                          1H-s-triazolo[4,3-a][1,5]-                                  1,5-benzodiazepin-4-one                                                                         benzodiazepine-1,5-dione                                17. 2-(methylthio)-7-chloro-                                                                        8-chloro-6-(2-methoxyphenyl)-                               5-(2-methoxyphenyl)-3H-                                                                         1H-s-triazolo[4,3-a][1,5]-                                  1,5-benzodiazepin-4-one                                                                         benzodiazepine-1,5-dione                                18. 2-(methylthio)-7-chloro-                                                                        8-chloro-6-(3-methoxyphenyl)-                               5-(3-methoxyphenyl)-3H-                                                                         1H-s-triazolo[4,3-a][1,5]-                                  1,5-benzodiazepin-4-one                                                                         benzodiazepine-1,5-dione                                19. 2-(methylthio)-7-chloro-                                                                        8-chloro-6-(2-methylphenyl)-                                5-(2-methylphenyl)-3H-                                                                          1H-s-triazolo[4,3-a][1,5]-                                  1,5-benzodiazepin-4-one                                                                         benzodiazepine-1,5-dione                                20. 2-(methylthio)-7-chloro-                                                                        8-chloro-6-(3-methylphenyl)-                                5-(3-methylphenyl)-3H-                                                                          1H-s-triazolo[4,3-a][1,5]-                                  1,5-benzodiazepin-4-one                                                                         benzodiazepine-1,5-dione                                21. 2-(methylthio)-7-chloro-                                                                        8-chloro-6-(4-methylphenyl)-                                5-(4-methylphenyl)-3H-                                                                          1H-s-triazolo[4,3-a][1,5]-                                  1,5-benzodiazepin-4-one                                                                         benzodiazepine-1,5-dione                                22. 2-(methylthio)-3-methyl-                                                                        4-methyl-8-chloro-6-phenyl-                                 7-chloro-5-phenyl-3H-1,5-                                                                       1H-s-triazolo[4,3-a][1,5]-                                  benzodiazepin-4-one                                                                             benzodiazepin-1,5-dione                                 23. 2-(methylthio)-3-(benzyl-                                                                       4-(benzyloxy)-8-chloro-6-                                   oxy)-7-chloro-5-phenyl-                                                                         phenyl-1H-s-triazolo-                                       3H-1,5-benzodiazepin-4-                                                                         [4,3-a][1,5]benzodia-                                       one               zepin-1,5-dione                                         24. 2-(methylthio)-3-methoxy-                                                                       4-methoxy-8-chloro-6-phenyl                                 7-chloro-5-phenyl-3H-1,5-                                                                       1H-s-triazolo[4,3-a][1,5]-                                  benzodiazepin-4-one                                                                             benzodiazepin-1,5-dione                                 25. 2-(methylthio)-8-methyl-                                                                        9-methyl-6-phenyl-1H-s-                                     5-phenyl-3H-1,5-benzodia-                                                                       triazolo[4,3-a][1,5]benzo-                                  zepin-4-one       diazepin-1,5-dione                                      26. 2-(methylthio)-8-chloro-                                                                        9-chloro-6-phenyl-1H-s-                                     5-phenyl-3H-1,5-benzo-                                                                          triazolo[4,3-a][1,5]-                                       diazepin-4-one    benzodiazepin-1,5-dione                                 27. 2-(methylthio)-8-(tri-                                                                          9-(trifluoromethyl)-6-                                      fluoromethyl)-5-phenyl-                                                                         phenyl-1H-s-triazolo[ 4,3-a]-                               3H-1,5-benzodiazepin-                                                                           [1,5]benzodiazepin-1,5-dione                                4-one                                                                     ______________________________________                                    

EXAMPLES 28- 348-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione

Following the procedure of Example 1, Method B, but substituting thealkyl carbazates indicated below for ethyl carbazate in Example 1,Method B, gives the title compound.

28. methyl carbazate

29. propyl carbazate

30. isopropyl carbazate

31. butyl carbazate

32. isobutyl carbazate

33. secondary butyl carbazate

34. n-hexyl carbazate

EXAMPLE 35 2-(Methylthio)-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one

To 3.03 g of 7-chloro-5-phenyl-1H-1,5-benzodiazepin-4-one-2-thione in asolution of 0.40 g of sodium hydroxide and 15 ml of methanol is added,with stirring a solution of 1.4 g of methyl iodide in 10 ml of methanol.Stirring is continued for 1 hour, the reaction is then evaporated andsuspended in methylene chloride (30 ml). The suspension is filteredthrough a short Florisil column; the column is washed with ethyl acetateand the combined filtrates are evaporated. The residue is trituratedwith a minimum amount of absolute ethanol and the title compound isfiltered off and dried.

EXAMPLES 36- 39

Following the procedure of Example 35 but substituting the compoundsindicated in Column I below for methyl iodide and the compoundsindicated in Column II for7-chloro-5-phenyl-1H-1,5-benzodiazepin-4-one2-thione in Example 35, thebenzodiazepinones indicated in Column III are obtained

    __________________________________________________________________________            I            II                  III                                  __________________________________________________________________________    36. benzylbromide                                                                            7-(trifluoromethyl)-5-phenyl-                                                                  2-(benzylthio)-7-(trifluoromethyl)-                          1H-1,5-benzodiazepin-4-one-                                                                    5-phenyl-3H-1,5-benzodiazepin-                               2-thione         4-one                                         37. O-propyl p-toluene-                                                                      7-nitro-5-(o-chlorophenyl)-                                                                    2-(propylthio)-7-nitro-5-(o-                      sulfonate  1H-1,5-benzodiazepin-4-one-                                                                    chlorophenyl)-3H-1,5-benzodia-                               2-thione         zepin-4-one                                   38. methyl iodide                                                                            7-(trifluoromethyl)-5-phenyl-                                                                  2-(methylthio)-7-(trifluoromethyl)-                          1H-1,5-benzodiazepin-4-one                                                                     5-phenyl-3H-1,5-benzodiazepin-                               2-thione         4-one                                         39. diethyl sulfate                                                                          7-chloro-5-phenyl-1H-1,5-                                                                      2-(ethylthio)-7-chloro-                                      benzodiazepin-4-one-2-thione                                                                   5-phenyl-3H-1,5-benzodiazepin-                                                4-one                                         __________________________________________________________________________

EXAMPLES 40- 65

Following the procedure of Example 35 but substituting the compoundsindicated in Column I below for7-chloro-5-phenyl-1H-1,5-benzodiazepin-4-one-2-thione in Example 35, thecompounds indicated in Column II are obtained.

    ______________________________________                                               I               II                                                     ______________________________________                                        40. 5-phenyl-1H-1,5-                                                                              2-(methylthio)-5-phenyl-                                      benzodiazepin-4-one-                                                                          3H-1,5-benzodiazepin-                                         2-thione        4-one                                                     41. 7-(trifluoromethyl)-5-                                                                        2-(methylthio)-7-(tri-                                        phenyl-1H-1,5-benzo-                                                                          fluoromethyl)-5-phenyl-                                       diazepin-4-one-2-                                                                             3H-1,5-benzodiazepin-                                         thione          4-one                                                     42. 7-nitro-5-phenyl-                                                                             2-(methylthio)-7-nitro-                                       1H-1,5-benzodiazepin-                                                                         5-phenyl-3H-1,5-benzo-                                        4-one-2-thione  diazepin-4-one                                            43. 7-methyl-5-phenyl-1H-                                                                         2-(methylthio)-7-methyl-                                      1,5-benzodiazepin-4-                                                                          5-phenyl-3H-1,5-benzo-                                        one-2-thione    diazepin-4-one                                            44. 7-methoxy-5-phenyl-                                                                           2-(methylthio)-7-methoxy-                                     1H-1,5-benzodiazepin-                                                                         5-phenyl-3H-1,5-benzo-                                        4-one-2-thione  diazepin-4-one                                            45. 7-(methylthio)-5-                                                                             2,7-di(methylthio)-5-                                         phenyl-1H-1,5-benzo-                                                                          phenyl-3H-1,5-benzodia-                                       diazepin-4-one-2-                                                                             zepin-4-one                                                   thione                                                                    46. 7-pentyl-5-phenyl-1H-                                                                         2-(methylthio)-7-pentyl-5-                                    1,5-benzodiazepin-4-                                                                          phenyl-3H-1,5-benzodiazepin-                                  one-2-thione    4-one                                                     47. 7-pentoxy-5-phenyl-                                                                           2-(methylthio)-7-pentoxy-5-                                   1H-1,5-benzodiazepin-                                                                         phenyl-3H-1,5-benzodiazepin-                                  4-one-2-thione  4-one                                                     48. 7-bromo-5-phenyl-1H-                                                                          2-(methylthio)-7-bromo-5-                                     1,5-benzodiazepin-4-                                                                          phenyl-3H-1,5-benzodiazepin-                                  one-2-thione    4-one                                                     49. 7-fluoro-5-phenyl-                                                                            2-(methylthio)-7-fluoro-5-                                    1H-1,5-benzodiazepin-                                                                         phenyl-3H-1,5-benzodiazepin-                                  4-one-2-thione  4-one                                                     50. 7-cyano-5-phenyl-1H-                                                                          2-(methylthio)-7-cyano-5-                                     1,5-benzodiazepin-4-                                                                          phenyl-3H-1,5-benzodiazepin-                                  one-2-thione    4-one                                                     51. 7-chloro-5-(2-chloro-                                                                         2-(methylthio)-7-chloro-5-                                    phenyl)-1H-1,5-benzo-                                                                         (2-chlorophenyl)-3H-1,5-                                      diazepin-4-one-2-thione                                                                       benzodiazepin-4-one                                       52. 7-chloro-5-(2-fluoro-                                                                         2-(methylthio)-7-chloro-5-                                    phenyl)-1H-1,5-benzo-                                                                         (2-fluorophenyl)-3H-1,5-                                      diazepin-4-one-2-thione                                                                       benzodiazepin-4-one                                       53. 7-chloro-5-(3-chloro-                                                                         2-(methylthio)-7-chloro-5-                                    phenyl)-1H-1,5-benzo-                                                                         (3-chlorophenyl)-3H-1,5-                                      diazepin-4-one-2-thione                                                                       benzodiazepin-4-one                                       54. 7-chloro-5-(4-chloro-                                                                         2-(methylthio)-7-chloro-5-                                    phenyl)-1H-1,5-benzo-                                                                         (4-chlorophenyl)-3H-1,5-                                      diazepin-4-one-2-thione                                                                       benzodiazepin-4-one                                       55. 7-chloro-5-(2-methoxy-                                                                        2-(methylthio)-7-chloro-5-                                    phenyl)-1H-1,5-benzo-                                                                         (2-methoxyphenyl)-3H-1,5-                                     diazepin-4-one-2-thione                                                                       benzodiazepin-4-one                                       56. 7-chloro-5-(3-methoxy-                                                                        2-(methylthio)-7-chloro-5-                                    phenyl)-1H-1,5-benzo-                                                                         (3-methoxyphenyl)-3H-1,5-                                     diazepin-4-one-2-thione                                                                       benzodiazepin-4-one                                       57. 7-chloro-5-(2-methyl-                                                                         2-(methylthio)-7-chloro-5-                                    phenyl)-1H-1,5-benzo-                                                                         (2-methylphenyl)-3H-1,5-                                      diazepin-4-one-2-thione                                                                       benzodiazepin-4-one                                       58. 7-chloro-5-(3-methyl-                                                                         2-(methylthio)-7-chloro-5-                                    phenyl)-1H-1,5-benzo-                                                                         (3-methylphenyl)-3H-1,5-                                      diazepin-4-one-2-thione                                                                       benzodiazepin-4-one                                       59. 7-chloro-5-(4-methyl-                                                                         2-(methylthio)-7-chloro-5-                                    phenyl)-1H-1,5-benzo-                                                                         (4-methylphenyl)-3H-1,5-                                      diazepin-4-one-2-thione                                                                       benzodiazepin-4-one                                       60. 3-methyl-7-chloro-5-                                                                          2-(methylthio)-3-methyl-7-                                    phenyl-1H-1,5-benzo-                                                                          chloro-5-phenyl-3H-1,5-                                       diazepin-4-one-2-thione                                                                       benzodiazepin-4-one                                       61. 3-(benzyloxy)-7-chloro-                                                                       2-(methylthio)-3-(benzyloxy)-                                 5-phenyl-1H-1,5-benzo-                                                                        7-chloro-5-phenyl-3H-1,5-                                     diazepin-4-one-2-thione                                                                       benzodiazepin-4-one                                       62. 3-methoxy-7-chloro-5-                                                                         2-(methylthio)-3-methoxy-7-                                   phenyl-1H-1,5-benzo-                                                                          chloro-5-phenyl-3H-1,5-                                       diazepin-4-one-2-thione                                                                       benzodiazepin-4-one                                       63. 8-methyl-5-phenyl-1H-                                                                         2-(methylthio)-8-methyl-5-                                    1,5-benzodiazepin-4-                                                                          phenyl-3H-1,5-benzodiazepin-                                  one-2-thione    4-one                                                     64. 8-chloro-5-phenyl-1H-                                                                         2-(methylthio)-8-chloro-5-                                    1,5-benzodiazepin-4-                                                                          phenyl-3H-1,5-benzodiazepin-                                  one-2-thione    4-one                                                     65. 8-(trifluoromethyl)-5-                                                                        2-(methylthio)-8-(trifluoro-                                  phenyl-1H-1,5-benzodia-                                                                       methyl)-5-phenyl-3H-1,5-benzo-                                zepin-4-one-2-thione                                                                          diazepin-4-one                                            ______________________________________                                    

EXAMPLE 66 7-chloro-5-phenyl-1H-1,5-benzodiazepin-4-one-2-thione

A solution of 28.6 g of7-chloro-5-phenyl-1H-1,5-benzodiazepine-2,4-dione and 23.3 g ofphosphorus pentasulfide in 250 ml of pyridine is refluxed, withstirring, for 40 minutes under argon. The solvent is evaporated invacuo.

The residue is stirred in ice water and extracted with methylenechloride. The organic phase is washed consecutively with dilute aqueoushydrochloric acid, water and dried. The organic phase is filteredthrough a short column of neutral III alumina and the filtrateevaporated. The residue is triturated with a small amount of hot benzeneand the product filtered off and dried.

EXAMPLE 678-chloro-6-(2',4'-dichlorophenyl)-1H-s-triazolo[4,3-a][1,5]-benzodiazepine-1,5-dionePart A

20 g of 2',4',5-trichloro-2-nitrodiphenylamine in 100 ml of methanolcontaining 0.2 g of Raney nickel is hydrogenated at an initial hydrogenpressure of 7 atm. until three molar equivalents of hydrogen isconsumed. The suspension is filtered and the filtrate evaporated to givethe 2',4',5-trichloro-2-aminodiphenylamine.

Part B

To a stirred refluxing solution of 28.7 of the above produced2',4',5-trichloro-2-aminodiphenylamine in 400 ml benzene is added,dropwise, a solution of 13.8 g of malonyl dichloride in 45 ml benzene.After addition is complete the reaction was refluxed for 7 hours,concentrated to 1/2 the original volume and cooled. The product,7-chloro-(2',4'-dichlorophenyl)-1H-1,5-benzodiazepin-2,4-dione, isfiltered off and dried.

Part C

Following the procedure of example 66 but substituting the aboveproduced7-chloro-5-(2',4'-dichlorophenyl)-1H-1,5-benzodiazepin-2,4-dione for7-chloro-5-phenyl-1H-1,5-benzodiazepine-2,4-dione in example 66, gives7-chloro-5-(2',4'-dichlorophenyl)-1H-1,5-benzodiazepin-4-one-2-thione.

Part D

Following the procedure of example 35 but substituting the aboveproduced7-chloro-5-(2',4'-dichlorophenyl)-1H,1,5-benzodiazepin-4-one-2-thionefor 7-chloro-5-phenyl-1H-1,5-benzodiazepin-4-one-2-thione in example 35,gives2-(methylthio)-7-chloro-5-(2',4'-dichlorophenyl)-3H-1,5-benzodiazepin-4-one.

Part E

Following the procedure of example 1, Method B, but substituting theabove produced2-(methylthio)-7-chloro-5-(2',4'-dichlorophenyl)-3H-1,5-benzodiazepin-4-onefor 2-(methylthio)-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one inexample 1, Method B, gives the title compound of formula 1.

EXAMPLES 68- 88

Following the procedure of part A to E of the foregoing example butemploying as starting materials the substituted compounds of formula 10wherein the substituents and the position they occupy are indicatedbelow:

    __________________________________________________________________________    Example                                                                       No.  3   4    5   6   2'   3' 4'   5'  6'                                     __________________________________________________________________________    68.      Cl   Cl                                                              69.  Cl                                                                       70.      Cl                   CH.sub.3 SO.sub.2                               71.      CF.sub.3     Cl           CF.sub.3                                   72.           Cl      CH.sub.3                                                                              CH.sub.3                                        73.           Cl      CH.sub.3                                                                              Cl                                              74.           Cl      CH.sub.3                                                                           CH.sub.3                                           75.           Cl      Cl                                                      76.      Cl       Cl                                                          77.      CH.sub.3 O                                                                         CH.sub.3 O                                                      78.      Cl   Cl           Cl                                                 79.      Cl           OCH.sub.3    OCH.sub.3                                  80.               Cl                                                          81.                   Cl   Cl                                                 82.  CH.sub.3 O   CH.sub.3 O                                                  83.      Cl   CH.sub.3                                                        84.      CH.sub.3 SO.sub.2                                                    85.      Cl           CH.sub.3 S                                              86.      Cl           CH.sub.3 SO.sub.2                                       87.           Cl      F                F                                      88.      Cl           F                F                                      __________________________________________________________________________

there is obtained the correspondingly substituted compound of formula Iwherein R¹ =hydrogen and wherein the substituents and the position theyoccupy are indicated below:

    __________________________________________________________________________    Example                                                                       No.  7   8   9    10  2'  3'  4'   5'  6'                                     __________________________________________________________________________    68.      Cl  Cl                                                               69.               Cl                                                          70.          Cl               CH.sub.3 SO.sub.2                               71.          CF.sub.3 Cl           CF.sub.3                                   72.      Cl           CH.sub.3                                                                              CH.sub.3                                        73.      Cl           CH.sub.3                                                                              Cl                                              74.      Cl           CH.sub.3                                                                          CH.sub.3                                            75.      Cl           Cl      CH.sub.3                                        76.  Cl      Cl                                                               77.      CH.sub.3 O                                                                        CH.sub.3 O                                                       78.      Cl  Cl               Cl                                              79.          Cl       OCH.sub.3    OCH.sub.3                                  80.  Cl                                                                       81.                   Cl  Cl                                                  82.  OCH.sub.3    OCH.sub.3                                                   83.      CH.sub.3                                                                          Cl                                                               84.          CH.sub.3 SO.sub.2                                                85.          Cl       SCH.sub.3                                               86.          Cl       CH.sub.3 SO.sub.2                                       87.      Cl           F                F                                      88.          Cl       F                F                                      __________________________________________________________________________

EXAMPLE 89 4-Hydroxy-8-chloro-6-phenyl-1H-s-triazolo-[4,3-a][1,5]benzodiazepine-1,5-dione

44.6 g of4-(benzyloxy)-8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dionein 400 ml of ethanol containing 2.0 g of 10% palladium-on-charcoal ishydrogenated at an initial hydrogen pressure of 40 p.s.i. After 0.1 moleof hydrogen has been absorbed, the reaction is stopped, filtered and thesolvent evaporated. The residue is triturated with ether and the titlecompound filtered off and dried.

EXAMPLE 908-(methylsulfinyl)-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione

3.22 g of 8-(methylthio)-6-phenyl-1H-s-triazolo [4,3-a][1,5]benzodiazepine-1,5 -dione and 2.14 g of sodium metaperiodate in 500ml methanol is stirred at +5° C. for 24 hours. The reaction isevaporated; the residue dissolved in methylene chloride, washed withwater, dried and concentrated. The concentrate is chromotographed ontwenty silica gel (1000μ plates, 20× 20 cm) using acetone-methanol (9:1)as eluting solvent. the band containing the product is removed, stirredwith acetone-methanol (4:1) and the silica gel filtered off. Thefiltrate is evaporated to give the title compound.

EXAMPLE 91 8-amino-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione

33.5 g of 8-nitro-6-phenyl-1H-s-triazolo[4,3-a][1,5]-benzodiazepine-1,5-dione in 100 ml of ethanol containing 2.0 g of10% palladium-on-charcoal is hydrogenated at room temperature at aninitial hydrogen pressure of 50 p.s.i. The reaction is stopped when 0.3moles of hydrogen has been absorbed; the suspension is filtered and thefiltrate evaporated to give the title compound.

EXAMPLE 92 8-acetamido-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione

2.91 g of 8-amino-6-phenyl-1H-s-triazolo[4,3-a][1,5]-benzodiazepine-1,5-dione and 1.02 g of acetic anhydride in 50 mlpyridine is stirred for 12 hours then refluxed for 30 minutes. Thereaction is evaporated; the residue is taken up in chloroform, washedwith dilute aqueous sodium bicarbonate, with water and dried. Thesolvent is evaporated to give the title compound.

EXAMPLE 93 8-(methylsulfonyl)-6-phenyl-1H-s-triazolo[4,3-a][1,5]-benzodiazepine-1,5-dione

Following the procedure of example 90, but using 4.14 g instead of 2.14g of sodium metaperiodate, the title compound is obtained.

EXAMPLE 94 2-Methyl-8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5-benzodiazepin-1,5-dione

To an ice-cooled, stirred solution of 3.7 g of8-chloro-6-phenyl-1H-s-triazolo[4,3-a] [1,5]benzodiazepine-1,5-dione in100 ml of dried and distilled 1,2-dimethoxyethane, is added, in aportionwise manner, 0.57 g of a 57% dispersion of sodium hydride inmineral oil. After the evolution of hydrogen has ceased (15 min), asolution of 1.79 g (0.014 mole) of methyl iodide is added, the ice bathremoved and stirring continued at room temperature for 2 hours, followedby heating under reflux for 1 hour. The solvent is then removed bydistillation. The residue is dissolved in 100 ml of chloroform, washedtwice with 100 ml portions of water, dried and concentrated. Treatmentof the residue with a small amount of ether precipitates the titlecompound which is filtered off, dried and recrystallized from ethylacetate.

EXAMPLE 95- 101

Following the procedure of example 94 but substituting the compoundsindicated in column I below for methyl iodide in example 94, thecompounds indicated in column II are obtained:

    ______________________________________                                        I                     II                                                      ______________________________________                                        95.  3-dimethylaminopropyl                                                                         2-(3-dimethylaminopropyl)-                                    chloride        8-chloro-6-phenyl-1H-s-                                                       triazolo[4,3-a][1,5]benzodia-                                                 zepine-1,5-dione                                         96.  2-diethylaminoethyl                                                                           2-(2-diethylaminoethyl)-8-                                    bromide         chloro-6-phenyl-1H-s-triazolo-                                                [4,3-a][1,5]benzodiazepine-                                                   1,5-dione                                                97.  2-dimethylaminoethyl                                                                          2-(2-dimethylaminoethyl)-8-                                   chloride        chloro-6-phenyl-1H-s-triazolo-                                                [4,3-1][1,5]benzodiazepine-                                                   1,5-dione                                                98.  3-diethylaminopropyl                                                                          2-(3-diethylaminopropyl)-8-                                   chloride        chloro-6-phenyl-1H-s-triazolo-                                                [4,3-a][1,5]benzodiazepine-                                                   1,5-dione                                                99.  Benzyl bromide  2-benzyl-8-chloro-6-phenyl-                                                   1H-s-triazolo[4,3-a][1,5]-                                                    benzodiazepine-1,5-dione                                 100. p-chlorophenethyl                                                                             2-(p-chlorophenethyl)-8-chloro-                               chloride        6-phenyl-1H-s-triazolo[4,3-a]-                                                [1,5]benzodiazepine-1,5-                                                      dione                                                    101. 2-(N-benzyl-N-methyl-                                                                         2-[2-(N-benzyl-N-methylamino)-                                amino)ethyl chloride                                                                          ethyl]-8-chloro-6-phenyl-1H-                                                  s-triazolo[4,3-a][1,5]benzodia-                                               zepine-1,5-dione                                         102. 3-[(t-butoxycarbonyl)-                                                                        2-[3-[(t-butoxycarbonyl)amino]-                               amino]propyl chloride                                                                         propyl]-8-chloro-6-phenyl-1H-                                                 s-triazolo[4,3-a][1,5]benzo-                                                  diazepine-1,5-dione                                      ______________________________________                                    

EXAMPLE 1032-(2-Methylaminopropyl)-8-chloro-6-phenyl-1H-s-triazolo-[4,3-a][1,5]benzodiazepine-1,5-dione

4 g of2-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione in 100 ml of ethanol containing 0.4 g of5% palladium on charcoal is hydrogenated at 50 p.s.i. hydrogen pressureuntil 1 molar equivalent of hydrogen is absorbed. The suspension isfiltered and the filtrate is evaporated. The residue is triturated witha small amount of cold ether and the title compound is filtered off anddried.

EXAMPLE 104 2-(3-aminopropyl)-8-chloro-6-phenyl-1H-s-triazolo[4,3a][1,5]-benzodiazepine-1,5-dione

2.5 g of2-[3-(t-butoxycarbonylamino)propyl]-8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dionein 50 ml of trifluoroacetic acid is stirred at room temperature for 2hours. The reaction is evaporated and the residue is stirred with asolution of 1.9 g of sodium bicarbonate in 400 ml of methanol-water(10:1). After 3 hours the reaction is evaporated and the residue ispartitioned between methylene chloride and water. The methylene chlorideis washed with water, dried and evaporated to give the title compound.

EXAMPLES 105- 111

Following the procedure of Example 94 but substituting the compoundsindicated in Column I below for 8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione in Example 94, the compounds indicated inColumn II are obtained.

    ______________________________________                                                I              II                                                     ______________________________________                                        105. 6-phenyl-1H-s-triazolo-                                                                       2-methyl-6-phenyl-1H-s-                                       [4,3-a][1,5]benzodia-                                                                         triazolo[4,3-a][1,5]benzo-                                    zepine-1,5-dione                                                                              diazepine-1,5-dione                                      106. 8-(trifluoromethyl)-6-                                                                        2-methyl-8-(trifluoromethyl)-                                 phenyl-1H-s-triazolo-                                                                         6-phenyl-1H-s-triazolo[4,3-a]-                                [4,3-a][1,5]benzodia-                                                                         [1,5]benzodiazepine-1,5-                                      zepine-1,5-dione                                                                              dione                                                    107. 8-nitro-6-phenyl-1H-                                                                          2-methyl-8-nitro-6-phenyl-                                    s-triazolo[ 4,3-a][1,5]-                                                                      1H-s-triazolo[4,3-a][1,5]-                                    benzodiazepine-1,5-                                                                           benzodiazepine-1,5-dione                                      dione                                                                    108. 8-methyl-6-phenyl-1H-                                                                         2,8-dimethyl-6-phenyl-                                        s-triazolo[4,3-a][1,5]-                                                                       1H-s-triazolo[4,3-a][1,5]-                                    benzodiazepine-1,5-                                                                           benzodiazepine-1,5-dione                                      dione                                                                    109. 8-methoxy-6-phenyl-1H-                                                                        2-methyl-8-methoxy-6-phenyl-                                  s-triazolo[4,3-a][1,5]-                                                                       1H-s-triazolo[4,3-a][1,5]-                                    benzodiazepine-1,5-                                                                           benzodiazepine-1,5-dione                                      dione                                                                    110. 8-(methylthio)-6-phenyl-                                                                      2-methyl-8-(methylthio)-6-                                    1H-s-triazolo[4,3-a]-                                                                         phenyl-1H-s-triazolo[4,3-a]-                                  [1,5]benzodiazepine-                                                                          [1,5]benzodiazepine-1,5-                                      1,5-dione       dione                                                    111. 4-benzyloxy-8-chloro-                                                                         2-methyl-(4-benzyloxy-8-                                      6-phenyl-1H-s-triazolo-                                                                       chloro)-6-phenyl-1H-s-triazolo                           [4,3-a][1,5]benzodia-                                                              [4,3-a][1,5]benzodiazepine-                                                   zepine-1,5-dione                                                                              1,5-dione                                                ______________________________________                                    

EXAMPLE 112 2-Methyl-4-hydroxy-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione

Following the procedure of example 89 but substituting2-methyl-4-(benzyloxy)-8-chloro-6-phenyl-1H-s-triazolo[4,3-a]-[1,5]benzodiazepine-1,5-dionefor 4-(benzyloxy)-8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione in Example 89, the title compound isobtained.

EXAMPLE 113 4-acetoxy-8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione

3.4 g of 4-hydroxy-8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione and 1.0 g of acetic anhydride in 10 ml ofpyridine are warmed in a steam bath for 0.2 hour and stirred at roomtemperature for 10 hours. The reaction mixture is cooled, diluted with100 ml of methylene chloride and washed with 100 ml water containing0.84 g sodium bicarbonate. The organic phase is washed four times withwater, dried and evaporated. The residue is triturated with a minimumamount of ether and the title compound filtered off, dried andrecrystallized from methylene chloride and ether.

EXAMPLE 114 8-Chloro-2,6-diphenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione

A mixture of 8.2 g of8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione, 5 gof copper powder and 2.5 g of potassium acetate in 100 ml ofbromobenzene are refluxed for six hours with stirring. The reaction isdiluted with methylene chloride, filtered through a short Florisilcolumn and the filtrate washed with dilute aqueous ammonium hydroxide.The organic phase is washed with water, dried and the solvent evaporatedto give the title compound.

EXAMPLES 115- 119

Following the procedure of example 114 but substituting the compoundsindicated in Column I below for 8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione in Example 114, the compounds indicated inColumn II are obtained.

    ______________________________________                                                I              II                                                     ______________________________________                                        115. 8-(trifluoromethyl)-6-                                                                        8-(trifluoromethyl)-2,6-                                      phenyl-1H-s-triazolo-                                                                         diphenyl-1H-s-triazolo-                                       [4,3-a][1,5]benzodia-                                                                         [4,3-a][1,5]benzodiazepine-                                   zepine-1,5-dione                                                                              1,5-dione                                                116. 8-nitro-6-phenyl-1H-                                                                          8-nitro-2,6-diphenyl-1H-                                      s-triazolo[4,3-a][1,5]-                                                                       s-triazolo[4,3-a][1,5]-                                       benzodiazepine-1,5-                                                                           benzodiazepine-1,5-dione                                      dione                                                                    117. 8-bromo-6-phenyl-1H-                                                                          8-bromo-2,6-diphenyl-1H-                                      s-triazolo[4,3-a][1,5]-                                                                       s-triazolo[4,3-a][1,5]-                                       benzodiazepine-1,5-dione                                                                      benzodiazepine-1,5-dione                                 118. 9-chloro-6-phenyl-1H-                                                                         9-chloro-2,6-diphenyl-1H-                                     s-triazolo[4,3-a][1,5]-                                                                       s-triazolo[4,3-a][1,5]-                                       benzodiazepine-1,5-                                                                           benzodiazepine-1,5-dione                                      dione                                                                    119. 8-chloro-6-(o-chloro-                                                                         8-chloro-2-phenyl-6-(o-                                       phenyl)-1H-s-triazolo-                                                                        chlorophenyl)-1H-s-triazolo-                                  [4,3-a][1,5]benzodia-                                                                         [4,3-a][1,5]benzodiazepine-                                   zepine-1,5-dione                                                                              1,5-dione                                                ______________________________________                                    

EXAMPLES 120- 124

Following the procedure of Example 114 but substituting the compoundsindicated in Column I below for8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione inexample 114, and substituting o-chlorobromobenzene for bromobenzene inexample 114, the compounds indicated in Column II are obtained.

    ______________________________________                                                I              II                                                     ______________________________________                                        120. 8-chloro-6-phenyl-1H-                                                                        8-chloro-2-(o-chlorophenyl)-                                   s-triazolo[4,3-a][1,5]-                                                                      6-phenyl-1H-s-triazolo[4,3-a]-                                 benzodiazepine-1,5-                                                                          [1,5]benzodiazepine-1,5-                                       dione          dione                                                     121. 8-(trifluoromethyl)-6-                                                                       8-(trifluoromethyl)-2-(o-                                      phenyl-1H-s-triazolo-                                                                        chlorophenyl)-6-phenyl-1H-                                     [4,3-a][1,5]benzodia-                                                                        s-triazolo[4,3-a][1,5]-                                        zepine-1,5-dione                                                                             benzodiazepine-1,5-dione                                  122. 8-nitro-6-phenyl-1H-                                                                         8-nitro-2-(o-chlorophenyl)-                                    s-triazolo[4,3-a][1,5]-                                                                      6-phenyl-1H-s-triazolo-                                        benzodiazepine-1,5-                                                                          [4,3-a][1,5]benzodiazepine-                                    dione          1,5-dione                                                 123. 8-bromo-6-phenyl-1H-                                                                         8-bromo-2-(o-chlorophenyl)-                                    s-triazolo[4,3-a][1,5]-                                                                      6-phenyl-1H-s-triazolo-                                        benzodiazepine-1,5-                                                                          [4,3-a][1,5]benzodiazepine-                                    dione          1,5-dione                                                 124. 8-chloro-6-(o-chloro-                                                                        8-chloro-2,6-di(o-chloro-                                      phenyl)-1H-s-triazolo-                                                                       phenyl)-1H-s-triazolo[4,3-a]-                                  [4,3-a][1,5]benzodia-                                                                        [1,5]benzodiazepine-1,5-                                       zepine-1,5-dione                                                                             dione                                                     ______________________________________                                    

EXAMPLE 1253-(7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one-2-yl)-carbazic acidethyl ester Method A

3.2 g of 2-(methylthio)-7-chloro-5-phenyl-1H-1,5-benzodiazepin-4-one and1.8 g of ethyl carbazate in 100 ml ethanol is refluxed for 14 hours.During this time a slow stream of nitrogen is bubbled through thereaction mixture. The mixture is evaporated, the residue taken up inmethylene chloride, washed with water, dried and the solvent evaporated.The residue is chromatographed on ten 1000μ silica gel plates (20× 20cm) with acetone-methanol (9:1) eluant. The band containing the productis removed and stirred with acetone-methanol (4:1). The silica gel isfiltered off and the filtrate evaporated to give the title compound.

Method B

2.8 g of 2-hydrazino-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one and1.1 g of ethyl chloroformate in 25 ml of triethylamine is stirred atroom temperature for 10 hours. The reaction mixture is evaporated andpartitioned between 100 ml methylene chloride and a solution of 0.84 gsodium bicarbonate in 50 ml water. The organic phase is dried andevaporated.

EXAMPLE 126

    ______________________________________                                        Preparation of capsule formulation                                            ______________________________________                                        Ingredient            Milligrams per Capsule                                  ______________________________________                                        8-chloro-6-phenyl-1H-s-triazolo-                                              [4,3-a][1,5]benzodiazepine-1,5-dione                                                                400                                                     Starch                80                                                      Magnesium stearate     5                                                      ______________________________________                                    

The active ingredient, starch and magnesium stearate are blendedtogether. The mixture is used to fill hard shell capsules of a suitablesize at a fill weight of 485 milligrams per capsule.

EXAMPLE 127 Preparation of tablet formulation

    ______________________________________                                        Preparation of tablet formulation                                             ______________________________________                                        Ingredient            Milligrams per Tablet                                   ______________________________________                                        8-chloro-6-(2'-chlorophenyl)-1H-s-tria-                                       zolo[4,3-a][1,5]benzodiazepine-1,5-dione                                                            300                                                     Lactose               200                                                     Corn starch (for mix)  50                                                     Corn starch (for paste)                                                                              50                                                     Magnesium stearate     6                                                      ______________________________________                                    

The active ingredient, lactose and corn starch (for mix) are blendedtogether. The corn starch (for paste) is suspended in water at a ratioof 10 grams of corn starch per 80 milliliters of water and heated withstirring to form a paste. This paste is then used to granulate the mixedpowders. The wet granules are passed through a No. 8 screen and dried at120° F. The dry granules are passed through a No. 16 screen. The mixtureis lubricated with magnesium stearate and compressed into tablets in asuitable tableting machine. Each tablet contains 300 milligrams ofactive ingredient.

EXAMPLE 128 Preparation of oral syrup formulation

    ______________________________________                                        Preparation of oral syrup formulation                                         ______________________________________                                        Ingredient                Amount                                              ______________________________________                                        2-Methyl-8-chloro-6-phenyl-1H-s-triazolo-                                     [4,3-a][1,5]benzodiazepin-1,5-dione                                                                     500 mg.                                             Sorbitol solution (70% N.F.)                                                                            40 ml.                                              Sodium benzoate           150 mg.                                             Sucaryl                   90 mg.                                              Saccharin                 10 mg.                                              Red Dye (F.D. & Co. No. 2)                                                                              10 mg.                                              Cherry flavor             50 mg.                                              Distilled water gs to     100 ml.                                             ______________________________________                                    

The sorbitol solution is added to 40 milliliters of distilled water andthe active ingredient is suspended therein. The sucaryl, saccharin,sodium benzoate, flavor and dye are added and dissolved in the abovesolution. The volume is adjusted to 100 milliliters with distilledwater.

Other ingredients may replace those listed in the above formulation. Forexample, a suspending agent such as bentonite magma, tragacanth,carboxymethylcellulose, or methylcellulose may be used. Phosphates,citrates or tartrates may be added as buffers. Preservatives may includethe parabens, sorbic acid and the like and other flavors and dyes may beused in place of those listed above.

What is claimed is:
 1. A compound of the formula ##STR13## wherein R' isH; phenyl optionally substituted by a member selected from the groupconsisting of alkyl of 1-3 carbons or alkoxy of 1-3 carbons, halogen,trifluoromethyl or nitro; or alkyl of 1-3 carbons optionally substitutedby a member selected from the group consisting of amino, mono-alkylaminoof 1-3 carbons or di-alkylamino wherein each alkyl radical contains 1-3carbons, or phenyl optionally substituted by alkyl of 1-3 carbons oralkoxy of 1-3 carbons, halogen, trifluoromethyl, or nitro;R² is H, alkylof 1-3 carbons, hydroxy or alkanoyloxy of 1-4 carbons; X occupies the 8-and/or 9-positions and is selected from the group consisting of H, F,Cl, Br, trifluoromethyl, alkyl of 1-4 carbons or alkoxy of 1-4 carbons,nitro, cyano, amino, alkanoylamino of 1-4 carbons, alkylthio of 1-4carbons, alkylsulfinyl of 1-4 carbons or alkyl sulfonyl of 1-4 carbons;Y may be the same as or different from X and occupies one or two of the2'-, 4'-, or 5'-positions and is selected from the group consisting ofH, F, Cl, trifluoromethyl, alkyl of 1-4 carbons or alkoxy of 1-4carbons, alkylthio of 1-4 carbons or alkyl sulfonyl of 1-4 carbons; andn is 0, 1 or
 2. 2. A compound of claim 1 wherein R' is H or --CH₃ and R²is H.
 3. A compound of claim 1 wherein n is 1 and X occupies the8-position and is chloro or bromo, trifluoromethyl or nitro.
 4. Acompound of claim 1 wherein n is 1 and Y occupies the 2'-position and ischloro or fluoro, or wherein n is 2 and Y occupies the 2'- and6'-positions and is fluoro in each case.
 5. A compound of claim 4wherein R' is H or CH₃, R² is H, n is 1 and X occupies the 8-positionand is chloro, bromo, trifluoromethyl or nitro.
 6. A compound of claim 1having the name8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione. 7.A compound of claim 1 having the name8-chloro-6-(2'-chlorophenyl)-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione.8. A compound of claim 1 having the name2-methyl-8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepin-1,5-dione.9. A compound of claim 1 having the name2-[2-(dimethylamino)ethyl]-8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]-benzodiazepine-1,5-dione.10. A compound of claim 1 having the name2-[3-(dimethylamino)propyl]-8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]-benzodiazepine-1,5-dione.11. A compound of the formula ##STR14## wherein R₁ is hydrogen, alkyl of1 to 3 carbon atoms, alkyl of 1 to 3 carbon atoms substituted by amember selected from the group consisting of amino, monoalkylamino of 1to 3 carbon atoms and dialkylamino wherein each alkyl radical has 1 to 3carbon atoms;R₂ is hydrogen or alkyl of 1 to 3 carbon atoms; R₃ and R₄are each independently hydrogen, F, Cl, Br, nitro, trifluoromethyl,alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or alkylthioof 1 to 4 carbon atoms; and n is 0, 1 or
 2. 12. The process forpreparing a compound of the formula ##STR15## wherein R₂ is hydrogen oralkyl of 1 to 3 carbon atoms; R₃ and R₄ are each independently,hydrogen, nitro, F, Cl, Br, trifluoromethyl, alkyl of 1 to 4 carbonatoms, alkoxy of 1 to 4 carbon atoms, or alkylthio of 1 to 4 carbonatoms; and n is 0, 1 or 2; which comprises reacting a compound of theformula ##STR16## wherein R₂ R₃, R₄ and n are as defined above, with acompound of the formula ##STR17## wherein R₅ is alkyl of 1 to 4 carbonatoms in an organic solvent at reflux to produce a compound of theformula ##STR18## wherein R₂, R₃, R₄, R₅ and n are as defined above;then heating in an organic solvent to produce the desired product.